RESEARCH IN HCV PROGRESSING AT A
FAST AND ENCOURAGING RATE

HIGHLIGHTS
FROM THE AASLD
LIVER MEETING
2019 FOCUS ON
HEPATITIS C

CONSULTING AUTHOR

Jordan J. Feld, MD, MPH
R. Phelan Chair in Translational
Liver Research
Toronto Centre for Liver Disease
Toronto General Hospital

Each year, the American Association for the Study of Liver Diseases (AASLD) holds one of the world’s premier hepatology congresses, The Liver Meeting®. This event represents a privileged platform during which scientists from around the globe share their latest research and results. The 2019 edition, held in Boston, MA, offered, as always, a rich and diverse program. Among one of the featured topics, research on the treatment and management of hepatitis C remained of the utmost importance, as reflected by the number of high-quality presentations on the subject.

The following review highlights some of the key presentations given on hepatitis C and hepatitis C virus (HCV) infections during the 2019 edition of The Liver Meeting®.

Effect of Direct-Acting Antivirals (DAA) on Long-Term Outcomes in Hepatitis C

With the advent of DAAs in 2011 came unparalleled efficacy in the treatment of HCV infection, which has drastically changed the hepatitis C treatment landscape. Most recently, the newest DAA’s are pan-genotypic covering all chronic hepatitis C individuals. With time, more and more data on the long-term effects of these drugs has become available and indicates that these agents provide a stable and long-lasting benefit.

One of the largest studies to assess the long-term benefits of DAA treatment was presented by Adeel Butt et al¹. The group used data from the ERCHIVES cohort of HCV infected Veterans to examine the effect of DAA regimens on liver-related mortality in people with HCV. Based on the analysis of records from over 60,000 HCV-infected patients, they concluded that DAA treatment significantly reduces the number of liver-related deaths not only when compared with untreated patients, but also when compared with patients treated with interferon (IFN)-based regimens. The greatest benefit is largely driven by the higher sustained virological response (SVR) rate observed in DAA-treated patients.

In a similar fashion, Jia Li et al². used data from 15,999 patients from the Chronic hepatitis Cohort Study (CHeCS) to compare the effect of SVR achievement from IFN-based or DAA therapy on cardiovascular and renal outcomes. Interestingly, their results indicated that while there were no differences in risk reduction of acute coronary syndrome or end-stage renal disease, DAA therapy increased risk reduction of ischemic stroke over IFN-based therapy in females, but not males.

Hepatocellular carcinoma (HCC) is one of the main long-term concerns in hepatitis C, HCV being the most common underlying aetiology in both the United States and Europe³. Still, the benefits of DAA therapy for HCV infections in patients with a history of HCC remain uncertain. Two important cohort studies recently addressed this question. Hansen Dang et al⁴. presented data on the impact of DAA treatment on 5-year survival rates in HCV-related HCC patients. Their study, which included 1676 patients from the US, Korea, Japan and Taiwan, concluded that patients who achieved SVR after treatment with DAAs had over 60-70% improvement in 5-year survival compared to patients untreated for HCV. In another large multicenter cohort study, Amit G. Singal et al⁵. compared overall survival between DAA‐treated and untreated HCV-infected patients who achieved a complete response to HCC treatment. They observed that DAA therapy was associated with significantly reduced mortality in patients with HCV-related HCC (HR 0.39, 95%CI 0.26–0.61), after adjusting for covariates.

Short-Course Treatment of HCV Infections

Shorter treatment regimens for HCV infections offer advantages in improving adherence and reducing costs. Importantly, shorter regimens also need to offer the same efficacy and safety as the 12-week regimens. Two studies presented at The Liver Meeting® 2019 explored the efficacy of shorter DAA regimens in specific populations: patients with acute and recently acquired HCV infections, and HCV patients with compensated cirrhosis.

The REACT Study⁶ is an international multicentre, open label, randomized phase 4 trial which compared the efficacy of sofosbuvir/velpatasvir (S/V) as short course (6 weeks) vs. standard duration (12 weeks) therapy in recently acquired HCV infection (≤12 months). While the full randomized dataset still needs to be analyzed, the preliminary results indicate that short course treatment with S/V was inferior to standard duration treatment. The study was stopped early due to high relapse rates in the 6 week arm.

The aim of the EXPEDITION – 8 study⁷ was to evaluate the safety and efficacy of an 8-week treatment with glecaprevir/pibrentasvir (G/P) in treatment-naive patients with chronic HCV genotype 1-6 (GT1-6) infection and compensated cirrhosis. The results show that 8-week treatment with G/P was associated with high sustained virological response (SVR-12) rates (≥ 97.7%). The treatment was overall well tolerated in the study population. While around 46% of patients experienced adverse events (AE), the most common being fatigue, pruritis, headache and nausea, no AE caused treatment discontinuation. These results led to the approval of this new treatment regimen for chronic HCV GT1-6 patients with compensated cirrhosis by the FDA.

Transplantation From HCV-Infected Donors

It is well known that there is a constant global shortage of organs available for transplantation. Unfortunately, an important number of potential organ donors get rejected due to increasing number of organ donors having HCV infection (HCV positive donor). However, the paradigm is currently shifting, as there is growing evidence that pre- and post-transplant treatment with DAA agents of HCV-infected organ recipients can prevent infection.

Karn Wijarnpreecha et al⁸ studied the use of HCV-seropositive donors to seronegative patients in 25 liver transplants. All patients received DAA treatment for a median time of 28 days after the graft; none of the patients developed detectable HCV viremia in the follow-up period (up to over a year), and short-term outcomes were otherwise deemed excellent.

In another study, Jordan Feld et al⁹. evaluated pre-emptive DAA therapy combined with a cholesterol absorption inhibitor (ezetimibe) that blocks HCV entry in hepatocytes, followed by 1 week of therapy to prevent or rapidly clear HCV infection. They followed 25 HCV-seronegative recipients who received organs (lung, kidney or heart) from HCV-viremic donors. Their results indicate that HCV infection was entirely prevented or rapidly cured in all recipients of HCV-infected organs. To note, one lung transplant patient died 10 weeks post-transplant of sepsis, but never had detectable HCV RNA. No other serious adverse events were reported, and medications were overall well tolerated.

HCV RNA in donors and recipients post-transplant

HCV in At-Risk Populations: Epidemiology and Prevention

Even if DAA treatment is highly effective to treat hepatitis C, prevention of first and subsequent HCV infections is a particular public health concern, especially among high-risk populations such as injection-drug users and people with risky sexual behaviours.

In a population cohort study, Naveed Janjua et al¹⁰ estimated HCV reinfection rates among DAA treatment users in British Columbia. Their results indicate that HCV reinfection rates after DAA therapy are significantly higher among people who inject drugs (PWID), especially in younger males. Interestingly, the authors also concluded that uninterrupted opioid-antagonist therapy (OAT) acted as a protective factor against reinfection.

HIV pre-exposure prophylaxis (PreP) has previously proven to be an efficient strategy to prevent HIV transmission among high-risk populations. However, there is concern that the use of HIV PrEP may lead to an increase in engagement in risky sexual behaviours. Tabatabavakili S et al¹¹. presented a study which aimed to determine whether the use of PrEP was associated with a higher incidence of HCV and other sexually transmitted infections (STI). It was found that HCV had a very low incidence rate in the study population, despite the very high rates for other STI that were observed, suggesting that the sexual transmission route may not be the predominance among high-risk population.

Cumulative incidence of HCV reinfection after DAA therapy in PWID and non-PWID

In order to prevent chronic HCV infections and potentially eradicate the virus, there is an essential need for a safe and efficient vaccine. Up to now, however, very little evidence is available regarding the efficacy of such an approach. Dr. Kimberly Page et al¹². presented the results of the first efficacy RCT for an HCV vaccine, which was realized among an at risk (injection drugs-using) population. While the results indicate that a prime-boost regimen did not provide protection against chronic infection, peak mean HCV RNA was significantly lower in the infected individuals who received the vaccine suggesting that immune responses at least partially controlled viral replication.

Effect of prime-boost HCV vaccine regimen on mean HCV RNA levels

DAA as a Second-Line Therapy for Hepatitis C

Despite the remarkable effectiveness of DAA treatment in real-world HCV care, treatment failures remain a challenge in disease eradication. Indeed, in some patients with chronic HCV infections, a single course of DAA treatment is insufficient to achieve SVR. Recent studies aim to evaluate the efficacy of second-line DAA treatment in hepatitis C.

Dr. Steven L. Flamm et al¹³. compared the efficacy of S/V/V and G/P in 231 patients who failed or relapsed following IFN-free DAA treatment. Significantly higher SVR rates were observed with S/V/V compared to G/P, both before and after adjustment for clinical differences. A similar, Canadian prospective study realized by De Quadros Onofrio F et al¹⁴. aimed to evaluate the efficacy of S/V/V (which is the recommended first-line treatment option for most patients) after at least one course of prior DAA treatment. Results indicate that S/V/V is highly effective as a salvage treatment HCV patient who failed to achieve SVR with prior treatment. Notably, patients who received S/V as a prior treatment were less likely to achieve SVR with S/V/V.

Conclusion

The 2019 AASLD Liver Meeting® continued to showcase that research in HCV is progressing at a fast and encouraging rate; DAA treatment is now widely used and has immensely improved the outcomes for patients. Of course, Hepatitis C remains an important public health challenge, and future efforts are trending toward simplification and standardization of treatment regimens as well as prevention of HCV infections on a large scale.

1. DAA Regimens are Associated with Significant Reduction in Liver Related Mortality Driven Largely by Higher SVR Rates: Results from the Erchives Cohort. Butt A et al. Abstract #0039. Presented at the AASLD Liver Meeting 2019.
2. Antiviral Treatment Status and Risk of Renal and Cardiovascular Outcomes in Patients with Chronic Hepatitis C. Li J et al. Abstract #0037. Presented at the AASLD Liver Meeting, Nov. 10, 2019.
3. Epidemiology of viral hepatitis and hepatocellular carcinoma. El-Serag HB. Gastroenterology. 2012; 142:1264–1273.e1.
4. HCV Cure by All Oral DAA Improves 5‐Year Overall and Liver‐Related Survival in HCV‐Related HCC Patients: A Real‐World, Propensity Score‐Matched Study from Both East and West. Dang H et al. Abstract #0040. Presented at the AASLD Liver Meeting, 2019.
5. Direct‐Acting Antiviral Therapy Is Associated With Improved Survival In Patients With A History Of Hepatocellular Carcinoma: A Multicenter North American Cohort Study. Singal AG et al. Abstract #0199. Presented at the AASLD Liver Meeting 2019.
6. Short course duration Sofosbuvir/Velpatasvir is inferior to standard duration therapy in the treatment of recently acquired HCV infection: results from REACT study. Matthews G. et al. Abstract #LP2. Presented at the AASLD Liver Meeting 2019.
7. Efficacy and safety of 8-week Glecaprevir/Pibrentasvir in treatment-naive patients with chronic hepatitis C virus genotype 1, 2, 3, 4, 5, or 6 infection and compensated cirrhosis: EXPEDITION-8 complete results. Brown Jr. RS et al. Abstract #LP9. Presented at the AASLD Liver Meeting 2019.
8. Multicenter Experience Evaluating Outcomes of HCV seropositive Donors to HCV‐Seronegative Recipients Liver Transplantation. Wijarnpreecha K. et al. Abstract #0003. Presented at the AASLD Liver Meeting 2019.
9. Transplantation From HCV‐Infected Donors to HCV Uninfected Recipients: Short Course Therapy to Prevent Transmission. Feld JJ et al. Abstract #0038. Presented at the AASLD Liver Meeting 2019.
10. Hepatitis C Virus Reinfection After Successful Treatment with Direct Acting Antiviral Therapy in Canada. Janjua N. et al. Abstract #0282. Presented at the AASLD Liver Meeting 2019.
11. Incidence of Hepatitis C Virus Infections Among Users of HIV Pre‐Exposure Prophylaxis in a Large Academic Centre in Toronto, Canada. Tabatabavakili S et al. Abstract #0281. Presented at the AASLD Liver Meeting 2019.
12. The first randomized, double-blind, placebo-controlled efficacy trial of vaccines to prevent chronic hepatitis C virus infection in an at-risk population. Page K et al. Abstract #LP17. Presented at the AASLD Liver Meeting 2019.
13. Pangenotypic Therapies Glecaprevir‐Pibrentasvir (G‐P) and Sofosbuvir‐Velpatasvir‐Voxilaprevir (S‐V‐V) after Failure with Interferon (IFN)‐Free Direct‐Acting Antiviral (DAA) Treatment for Hepatitis C. Flamm SL et al. Abstract #1500. Presented at the AASLD Liver Meeting 2019.
14. Prior Therapy with Sofosbuvir/Velpatasvir Associated with Reduced Response To Sofosbuvir/ Velpatasvir/Voxilaprevir: Results from a Canadian Prospective Registry. De Quadros Onofrio F et al. Abstract #1631. Presented at the AASLD Liver Meeting 2019.

This report was made possible through the support of AbbVie Corporation. The opinions and information contained herein are those of the author and do not necessarily reflect the views or opinions of AbbVie Corporation. Any products mentioned herein should be used in accordance with the approved prescribing information contained in their respective official product monograph.

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